Data from several sources support a link between changing environmental exposures and decreased male reproductive function, including a reported world-wide decline in semen quality over the past fifty years. Considerable geographic variability in sperm density has also been reported. However, to clearly identify real geographic and temporal differences in semen quality, studies with carefully controlled semen collection and analysis protocols, population selection, and control of confounding must first be carried out. Such controlled studies, which should precede any attempt to identify environmental causes of temporal and geographic variation in semen quality, have not yet been conducted. We propose, therefore, to conduct a multi-center study of semen and serum biomarkers of male reproductive function in partners of pregnant women, recruited from four urban U.S. centers. This proposed study would constitute the U.S. component of an international study of this design, begun in November 1996 in four European cities. Protocols and questionnaires in use in Europe will be adapted minimally, as necessary for U.S. populations. Morphology and motility analyses of semen from all U.S. centers will be conducted by a single technician at the Andrology Coordinating Center, U.C. Davis, and all slides will be reread for morphology by a single technician at the Andrology Coordinating Center in Paris. Serum analyses will be conducted by the Department of Growth and Reproduction, Copenhagen, without charge to the U.S. study. Strict quality control procedures have been instituted in Europe and will be utilized at all U.S. centers under the supervision of the Andrology Coordinating Center. The primary aim of our proposed study is to estimate geographic variability of semen parameters both within the U.S. and among eight European and U.S. cities. Our secondary aims are to study the geographic variability of serum hormones (testosterone, inhibin-B, luteinizing hormone, follicle stimulating hormone, sex hormone binding globulin and estradiol), as well as testicular and other physical abnormalities, and the relationships between these outcomes and semen quality. Finally, in order to evaluate health consequences of this variability, we propose to assess the strength of the relationships between these male reproductive parameters and time to conception, after controlling for confounding factors in both partners. We also propose to create a registry of male participants to study changes in male reproductive biomarkers in semen and serum prospectively, and to bank samples of serum and seminal fluid for assays of biomarkers of exposure and effect. An International Steering Committee, composed of study investigators from Europe and the U.S., will provide guidance and assure comparability of U.S. and European data. This is a unique opportunity to assess biomarkers of male reproduction across comparable populations in multiple centers in the U.S. and Europe, in a similar time period, using common protocols. This study should provide unbiased estimates of variability among cities which have been reported to differ widely in semen quality, provide baseline levels of male biomarkers for future studies, and generate hypotheses of environmental causes of variation in these parameters.